This invention relates to methods for inhibition of growth of transformed cells, and inhibition of progression to a transformed phenotype in pre-neoplastic cells.
Transformation is a cumulative process whereby normal control of cell growth and differentiation is interrupted, usually through the accumulation of mutations affecting the expression of genes that regulate cell growth and differentiation.
Scanlon WO91/18625, WO91/18624, and WO91/18913 describes a ribozyme effective to cleave oncogene RNA from the H-ras gene. This ribozyme is said to inhibit H-ras expression in response to exogenous stimuli. Reddy WO92/00080 describes use of ribozymes as therapeutic agents for leukemias, such as CML by targeting specific portions of the BCR-ABL gene transcript.
The epidermal growth factor (EGF) receptors have been implicated in human cancer more frequently than any other family of growth factor receptors. The EGF receptor gene is often amplified or overexpressed in squamous cell carcinomas and glioblastomas. Jenkins et al., 39 Cancer Genet. Cytogenet. 253,1989. Similarly, erbB-2 is often overexpressed in adenocarcinomas of the stomach, breast and ovary. Turc-Carel et. al., 12 ibid., 1, 1984. Overexpression of either gene under appropriate experimental conditions confers the transformed phenotype. Heim et. al., 32 ibid., 13, 1988. In certain breast carcinomas, the erbB-3 gene is overexpressed. Boehm et al., 7 EMBO J. 385, 1988.
The high incidence of human breast cancer has prompted efforts to model the disease in transgenic mice. The myc gene is amplified in some human breast cancers, Escot et. al., 83 Proc. Natl. Acad. Sci. USA 4834, 1986, and ras mutations have been observed. Barbacid. 56 Ann. Rev. Biochem. 779, 1987. Reproduction of disease by expression of the myc or ras genes in mice have given only sporadic results.
Breast cancer progression often correlates with amplification of the tyrosine kinase receptor gene denoted as c-erb-B2 or neu. The ligand for this receptor is unknown. Male and female mice expressing the neu gene both synchronously developed adenocarcinomas encompassing the entire gland. Muller et al., 54 Cell 105, 1988. Other strains developed tumors stochastically. Bouchard et al., 57 ibid., 931, 1989.